Myc, Aurora Kinase A, and mutant p53 R172H co-operate in a mouse model of metastatic skin carcinoma

E. C. Torchia, C. Caulin, S. Acin, T. Terzian, B. J. Kubick, N. F. Box, D. R. Roop

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying mechanisms. We have used two independent microarray platforms to perform a comprehensive and global analysis of tumors arising in a model of metastatic skin cancer progression, which compares the consequences of a GOF p53 R172H mutant vs p53 deficiency. DNA profiling revealed a higher level of genomic instability in GOF vs loss-of-function (LOF) p53 squamous cell carcinomas (SCCs). Moreover, GOF p53 SCCs showed preferential amplification of Myc with a corresponding increase in its expression and deregulation of Aurora Kinase A. Fluorescent in situ hybridization confirmed amplification of Myc in primary GOF p53 SCCs and its retention in metastatic tumors. We also identified by RNA profiling distinct gene expression profiles in GOF p53 tumors, which included enriched integrin and Rho signaling, independent of tumor stage. Thus, the progression of GOF p53 papillomas to carcinoma was marked by the acquisition of epithelial-to-mesenchymal transition and metastatic signatures. In contrast, LOF p53 tumors showed enrichment of genes associated with cancer proliferation and chromosomal instability. Collectively, these observations suggest that genomic instability has a prominent role in the early stages of GOF p53 tumor progression (that is, papillomas), whereas it is implicated at a later stage in LOF p53 tumors (that is, SCCs). This model will allow us to identify specific targets in mutant p53 SCCs, which may lead to the development of new therapeutic agents for the treatment of metastatic SCCs.

Original languageEnglish (US)
Pages (from-to)2680-2690
Number of pages11
JournalOncogene
Volume31
Issue number21
DOIs
StatePublished - May 2012
Externally publishedYes

Keywords

  • Aurora Kinase A
  • Myc
  • SCC
  • genomic instability
  • p53
  • tumor progression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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